Identification of a Novel Protein Kinase A Inhibitor by Bioluminescence-Based Screening.

We screened inhibitors in the adenylyl cyclase/protein kinase A/cAMP response element binding protein pathway (AC/PKA/CREB pathway) from a 2400 chemical library by a cell-based assay method using bioluminescence probes. We found a compound that inhibited forskolin-induced cAMP response element (CRE)-dependent transcription, the interaction between the kinase-inducible domain (KID) and the interacting domain (KIX), and endogenous CREB phosphorylation. Furthermore, this compound suppressed the activity of the PKA catalytic subunit dose-dependently. On the other hand, this compound did not inhibit forskolin-induced cAMP up-regulation. Taken together, we conclude that we have identified a new PKA inhibitor that binds to the catalytic subunit directly. We also succeeded in shortening the screening protocol by excluding a screening step which was used in a previous method.

Efficacy of immune checkpoint inhibitor therapy in patients with pulmonary sarcomatoid carcinoma in clinical practice.

OBJECTIVE: Studies have suggested the potential efficacy of immune checkpoint inhibitors (ICIs) for pulmonary sarcomatoid carcinoma. This multicenter observational study was conducted to evaluate the efficacy of systemic ICI therapy and chemoradiation followed by durvalumab therapy for pulmonary sarcomatoid carcinoma. METHODS: We analyzed the data of patients with pulmonary sarcomatoid carcinoma who received systemic ICI therapy or chemoradiation followed by durvalumab therapy between 2016 and 2022. RESULTS: In this study, data of a total of 22 patients who received systemic ICI therapy and four patients who received chemoradiation followed by durvalumab therapy were analyzed. In the patients who received systemic ICI therapy, the median progression-free survival after initiation of therapy was 9.6 months, and the overall survival did not reach the median. The 1-year progression-free survival rate and overall survival rate were estimated to be 45.5% and 50.1%, respectively. Although the log-rank test revealed no significant association between the tumor expression level of programmed death ligand-1 (tumor proportion score evaluated using 22C3 antibody: ≥50% vs. <50%) and the survival duration, the majority of patients showing long-term survival showed a tumor proportion score of ≥50%. Of four patients treated with chemoradiation followed by durvalumab therapy, two patients showed an overall survival of ≥30 months, whereas the remaining two patients died within 12 months. CONCLUSION: The progression-free survival of patients who received systemic ICI therapy was 9.6 months, suggesting that ICI therapy might be effective in patients with pulmonary sarcomatoid carcinoma.

Case Series of Pleomorphic Carcinoma of the Lung Treated With Immune Checkpoint Inhibitors.

AIM: We report, herein, three cases of pleomorphic carcinoma of the lung treated with immune checkpoint inhibitors. Case 1: A 73-year-old man was diagnosed as having pleomorphic carcinoma of the lung and treated with pembrolizumab alone. However, he showed no response and died 4 months after the initiation of the treatment. Case 2: A 66-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on a combination regimen of pembrolizumab plus carboplatin plus nab-paclitaxel, and a remarkable response was observed. Case 3: A 49-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on pembrolizumab monotherapy as second-line treatment. Eleven months after the treatment initiation, computed tomography revealed the decrease of tumor diameter. CONCLUSION: Immune checkpoint inhibitor therapy is expected to improve the prognosis of patients with pleomorphic carcinoma of the lung.

Immune Checkpoint Inhibitor for Non-small Cell Lung Cancer With Negative or Low Tumor PD-L1 Expression.

Background/Aim: We conducted a retrospective analysis of the survival durations of 25 patients diagnosed as having non-squamous cell non-small cell lung cancer with negative or low tumor programmed death-ligand 1 (PD-L1) expression treated with immune checkpoint inhibitor (ICI) monotherapy. Patients and Methods: The progression-free (PFS) and overall (OS) survival were calculated from the initiation of ICI monotherapy. The association between the patient characteristics and the PFS was analyzed using Cox proportional hazards model. Results: The median PFS was 2.6 months, and the 12-month PFS rate was 9.3%. The median OS was 5.5 months, and the 12-month OS rate was 39.8%. A Cox proportional hazards model identified the neutrophil/lymphocyte ratio and presence of liver metastasis as being significantly associated with PFS. Conclusion: Our findings suggest that a subset of patients with non-squamous cell non-small cell lung cancer who show negative or low tumor PD-L1 expression could benefit from ICI monotherapy.

Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice.

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality.

Cationic gold(I)-catalyzed intramolecular cyclization of gamma-hydroxyalkynones into 3(2H)-furanones.

The combination of (p-CF(3)C(6)H(4))(3)PAuCl and AgOTf generates a powerful catalyst for the intramolecular cyclizations of readily available gamma-hydroxyalkynones under mild conditions. The substituted 3(2H)-furanones are obtained in 55-94% yields. This method is also applicable to the preparation of 2,3-dihydro-4H-pyran-4-ones.

Association of Tumor PD-L1 Expression with the T790M Mutation and Progression-Free Survival in Patients with EGFR-Mutant Non-Small Cell Lung Cancer Receiving EGFR-TKI Therapy.

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), we compared the progression-free survival (PFS) and proportion of acquisition of T790M mutation of the epidermal growth receptor gene (EGFR) after first-line treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patient groups with and without tumor expression of programmed death ligand-1 (PD-L1). METHODS: Data of patients with EGFR-mutant NSCLC were retrospectively analyzed. Tumor PD-L1 expression was evaluated by immunohistochemistry using the 22C3 antibody. T790M gene mutation was evaluated by Cobas EGFR assay using tissues or humoral specimens. RESULTS: Data of 47 patients with EGFR-mutant NSCLC were analyzed. The median (95% confidence interval) PFS in the PD-L1-negative and -positive patient groups were 12.9 (9.7-15.4) months and 9.0 (5.1-12.3) months, respectively (p = 0.029). T790M gene mutation was analyzed in 27 patients. The proportion of acquisition of T790M mutation of EGFR after first-line treatment with an EGFR-TKI was higher in the PD-L1-negative patient group than in the PD-L1-positive patient group (8/11 patients (72.7%) vs. 4/16 patients (25.0%); p = 0.022). CONCLUSIONS: Patients with negative tumor PD-L1 expression showed longer PFS and a higher proportion of acquisition of T790M mutation of EGFR after first-line treatment with an EGFR-TKI.

Efficient intramolecular cyclizations of phenoxyethynyl diols into multisubstituted α,ß-unsaturated lactones.

AgOTf-catalyzed intramolecular cyclization of phenoxyethynyl diols proceeded under mild conditions to afford the multisubstituted α,ß-unsaturated-γ-lactones in 55-98% yields. This method was also applicable to the synthesis of α,ß-unsaturated-δ-lactones. A similar cyclization proceeded when AgOTf was replaced with a stoichiometric amount of N-bromosuccinimide to furnish the α-bromo-substituted α,ß-unsaturated lactones.

Cationic gold(I)-mediated intramolecular cyclization of 3-alkyne-1,2-diols and 1-amino-3-alkyn-2-ols: a practical route to furans and pyrroles.

The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amino-3-alkyn-2-ols with a low catalyst loading (0.05-0.5 mol %) of (Ph(3)P)AuCl-AgNTf(2) or (Ph(3)P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles in excellent yields (85-98% yields). This method is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol % each of the Au and Ag catalysts.